JPS6147823B2 - - Google Patents

Description

[Detailed description of the invention]

Butene-1 and chlorine are preferably added simultaneously to acetonitrile to produce a certain amount of by-products 1,2.
-Produces N-[1-(chloromethyl)propyl]acetimidoyl chloride with dichlorobutane; N-[1-(chloromethyl)propyl]
acetimidoyl chloride is conveniently hydrolyzed in situ to N-[1-(chloromethyl)propyl]acetamide, conveniently removing excess acetonitrile and 1,2-dichlorobutane;
dl-2-amino-1-butanol, conveniently as the hydrochloride salt, is prepared by further hydrolyzing it to dl-2-amino-1-butanol, possibly by a ring-closing and re-cleavage step. dl-2-
Amino-1-butanol has many uses as is, including its resolution to d-2-amino-1-butanol, which when reacted with ethylene dichloride produces ethambutol hydrochloride, d ，
This produces d'-2,2'-(ethylenediimino)di-1-butanol dihydrochloride. dl obtained by this method
-2-Amino-1-butanol yields ethambutol hydrochloride of excellent quality for pharmaceutical use. This process provides a particularly acceptable form for producing d,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochloride of excellent pharmaceutical quality by reaction with ethylene dichloride. d-2-amino-1-butanol is obtained. These expressions may be expressed as follows. N-[1-(chloromethyl)propyl]acetimidoyl chloride or N-[1-(chloromethyl)propyl]ethanimidoyl chloride N-[1-(chloromethyl)propyl]acetamide 4-ethyl-2-methyl-2-oxazoline hydrochloride or 4,5-dihydro-4-ethyl-2-
Methyl-oxazole hydrochloride dl-2-amino-1-butanol hydrochloride Surprisingly, in the reaction with acetonitrile, the best results are obtained when acetonitrile is used in excess. Although acetonitrile is an expensive ingredient, it is common practice to try to use less of the expensive ingredient. In this case chlorine is also butene-
1 to produce 1,2-dichlorobutane.
When acetonitrile is in excess, the reaction is reduced to N-[1
- (Chloromethyl)propyl] is pushed towards acetimidoyl chloride. N-[1-
(chloromethyl)propyl]acetimidoyl
An amount of water corresponding to the amount required for the hydrolysis of the chloride is added to the reaction mixture before, during or after the addition of chlorine and butene.
[1-(chloromethyl)propyl]acetimidoyl chloride may be hydrolyzed to N-[1-(chloromethyl)propyl]acetamide. The reaction between acetonitrile and the hydrochloric acid formed in the hydrolysis is sufficiently slow that at least 95% of the excess acetonitrile can be distilled from the reaction mixture under reduced pressure and recycled. Economic recovery of acetonitrile in a form that can be recycled into the process is important for low cost production efforts. Too much excess acetonitrile will require too large a reaction vessel. Continuous reactions may be used, allowing relatively small equipment and large excesses of acetonitrile, the latter of which is recycled to the starting material. If the hydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide is not completed during the reaction after stripping off the acetonitrile, Hydrolysis is completed by adding water to the pot residue. N-[1-
(chloromethyl)propyl]acetimidoyl
The production of N-[1-(chloromethyl)propyl]acetamide by hydrolysis of chloride can be obtained by hydrolysis of calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, barium carbonate or strontium carbonate. The presence of weak bases such as N-[1-(chloromethyl)propyl]acetamide is further hydrolyzed to form dl-2-
No base is required when preparing amino-1-butanol. After hydrolysis, 1,2-dichlorobutane is distilled off under reduced pressure. After removing acetonitrile and 1,2-dichlorobutane, the purity of N-[1-(chloromethyl)propyl]acetamide is such that it is of a quality that can be used for resolution steps or other purposes.
It is high enough to be conveniently processed into 1-butanol hydrochloride. N-[1-(chloromethyl)propyl]acetimidoyl chloride may be recovered and utilized after its formation. Advantageously, adding water to the reactor hydrolyzes N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide, effectively completing the first two steps. are carried out at the same time, providing better control of heat generation and saving time and handling since the processing steps are simultaneous. After chlorination is completed,
Water may be added in slight excess of the amount calculated to hydrolyze N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide. Acetonitrile may be decomposed from N-[1-(chloromethyl)propyl]acetimidoyl chloride or N-[1-(chloromethyl)propyl]acetamide. It is convenient to separate it hydrolyzed to N-[1-(chloromethyl)propyl]acetamide. After synthesis of N-[1-(chloromethyl)propyl]acetimidoyl chloride or after hydrolysis to N-[1-(chloromethyl)propyl]acetamide, 1,2-dichlorobutane is completely or partially separated by distillation. You may. At least a portion of the 1,2-dichlorobutane may be left until the synthesis of dl-2-amino-1-butanol hydrochloride is completed. N
It is usually more convenient to separate off the 1,2-dichlorobutane after hydrolysis to [1-(chloromethyl)propyl]acetamide. This is because the reaction mixture becomes smaller and N-[1-(chloromethyl)propyl]acetamide is reacted with dl-
This is because a more compact apparatus may be used to produce 2-amino-1-butanol hydrochloride. dl-2-amino-1- by azeotropic distillation with water
1,2-dichlorobutane can be conveniently and effectively completely removed from butanol. Methanol is then added to the aqueous reaction mixture containing N-[1-(chloromethyl)propyl]acetamide, preferably along with a catalytic amount of hydrochloric acid.
The hydrochloric acid is refluxed and hydrolyzed to produce dl-2-amino-1-butanol hydrochloride with by-product methyl acetate. When methyl acetate is removed by distillation,
dl-2-amino-1-butanol hydrochloride remains. The presence of water should be avoided in the preparation of N-[1-(chloromethyl)propyl]acetimidoyl chloride, and the presence of acetonitrile and 1,2-
Vacuum distillation is required to remove dichlorobutane. N-[1-(chloromethyl)propyl]
Upon hydrolysis to acetamide, mild conditions are preferred for the removal of both acetonitrile and 1,2-dichlorobutane. Weak bases aid in controlled hydrolysis. If hydrolysis to dl-2-amino-1-butanol is desired, the acid generated in the hydrolysis can be used to form the hydrochloride salt of the product. In the production of dl-2-amino-1-butanol hydrochloride, acetonitrile is recycled to N-
The [1-(chloromethyl)propyl]acetamide stage should be vacuum distilled. When acetonitrile is left behind during hydrolysis to dl-2-amino-1-butanol hydrochloride, acetonitrile yields ammonia, usually as ammonium chloride;
It tends to hydrolyze to acetic acid. Although the acetic acid produced in the hydrolysis of acetonitrile is easily removed as a methyl ester, the loss of acetonitrile reduces the efficiency of the process. N-[1-(Chloromethyl) Process] In the acetamide stage, it is preferred to remove at least a portion of the 1,2-dichlorobutane by vacuum distillation. This does not create any complications other than increasing the required reactor size. Conveniently, the last 1,2-dichlorobutane is removed by azeotropic distillation from dl-2-amino-1-butanol hydrochloride when acetic acid is removed as the methyl ester. Conveniently, the intermediate reaction to dl-2-amino-1-butanol hydrochloride was performed using N-[1-(chloromethyl)propyl]acetimidoyl chloride and N-
[1-(chloromethyl)propyl]acetamide can be duplicated without isolation. By dissolving in methyl alcohol or isopropanol or mixtures thereof, dl-
A solution of 2-amino-1-butanol was obtained mainly as the hydrochloride salt, which was partially neutralized with ammonia to form dl-2-amino-1-butanol and dl-
A mixture of 2-amino-1-butanol hydrochloride and ammonium chloride is formed, but the ammonium chloride is removed. The remaining mixture is approximately 2 parts
dl-amino-1-butanol and one part of dl-2-amino-1-butanol hydrochloride, as described in U.S. Pat.
As detailed in the specification of No. 3553257, the ratio is L(+)-- in the presence of anhydrous methanol.
Close to the optimal conditions desired for reaction with tartaric acid to allow separation of d-2-amino-1-butanol tartrate. This method has unique and unexpected advantages. This is because some of the butene-1 adds chlorine and acetonitrile in the opposite direction to the desired position, resulting in about 3-10% of dl-1-amino-2 as impurities in dl-2-amino-1-butanol.
-Because butanol is found. dl-2-
In the separation of the d- and l-isomers of amino-1-butanol, both isomers of dl-1-amino-2-butanol remain with the mother liquor, producing highly purified d-2-amino- 1-butanol is L
(+)-Separated as tartrate. Starting materials containing up to about 10% dl-1-amino-2-butanol may contain up to 0.01% dl-
Purified d-2-amino-1-butanol with 1-amino-2-butanol as its tartrate salt is produced. It can be present up to 0.1% if washing is insufficient. With further minimal additional purification, purity can easily be obtained for use as a starting material for pharmaceutical quality ethambutol. Ease of separation of impurities and by-products is not self-evident and is also the essence of this reaction system. Example 1 Preparation of N-[1-(chloromethyl)propyl]acetimidoyl chloride Reagents were placed in a 500 ml three-necked flask equipped with a mechanical stirrer, a low temperature thermometer, and an inlet tube filled with two glass bulbs. Add grade acenanitrile (82 g, 2 moles). Butene-1 (28
g, 0.5 mole) and chlorine (35.5 g, 0.5 mole) are added simultaneously. The addition is complete in about 37 minutes and at the end of this time the reaction temperature rises to -10°C (bath temperature -20°C). Fractional distillation of the mixture yields:
Distillate, 89 g (mainly acetonitrile) at 20 mm pressure and bath temperature 50 °C; Distillate 12.5 g, distillate at 20 mm pressure and bath temperature 65 °C, 1,2-dichlorobutane
70%, N-[1-(chloromethyl)propyl]acetimidoyl chloride 30%; distillate, 35.9 g
Distillation at a bath temperature of 60°C and a pressure of 2 mm, approximately 90% N-[1-(chloromethyl)propyl]acetimidoyl chloride; residual 6.7 g dark brown viscous oil. Based on the fraction and N-[1-(chloromethyl)
The yield of propyl]acetimidoyl chloride is
It is 39.7g (48g). Redistilling a portion of the fraction yields a pale yellow oil with a characteristic odor similar to thionyl chloride. The product N-(chloromethyl)propyl]acetimidoyl chloride is
3000, 1705, 1430, 1370, 1085, 960, 920, 840
and shows a strong infrared band at 740 cm ^-1 . NMR
( _CDCl3 ): 0.88ppm (t, 3H), 1.4~1.8ppm
(m, 2H), 245ppm (s, 3H), 3.62ppm (m,
2H, -CH ₂ Cl) and about 3.9ppm (m, 1H, CH). Often a solid isomer of N-[1-(chloromethyl)propyl]acetimidoyl chloride (often the main product) is also obtained. Both forms appear to be interchangeable in certain solvents.
When reacting with water, both hydrolyze to N-[1-(chloromethyl)propyl]acetamide. Solid ones are 3000, 1650, 1550, 14580, 1365,
It has infrared bands at 1280, 1045, and 740 cm ^-1 . Examples 2-8 The effect of various conditions on the yield is shown in the following examples, in which the chlorination reaction was carried out at temperatures from -3°C to +23°C above the initial temperature, and the Cl of acetonitrile was The ratio to ₂ was changed from 2 to 4. Furthermore, the initial concentration of butene-1 is
Either pass butene-1 and Cl ₂ into acetonitrile simultaneously (low initial concentration of butene-1) or first condense the butene in acetonitrile at -5°C and then pass Cl ₂ through the mixture (low initial concentration of butene-1). high initial concentration). The results of these tests in Table 1 show that the yield of N-[1-(chloromethyl)propyl]acetimidoyl chloride depends primarily on the molar ratio of acetonitrile to _Cl2 ;
It also shows that when this ratio is brought closer to 4, it becomes approximately 50-55%.

[Table] () I=N-[1-(chloromethyl)propyl]acetimidoyl chloride The hydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride is highly dependent on pH. It has now been found that a simple hydrolysis procedure is effective. Refluxing N-[1-(chloromethyl)propyl]acetimidoyl chloride with water produces dl-2-amino-1-butanol (77%) and dl-2-amino-1 within 1 hour.
-Butanol acetate hydrochloride (17%), N-
It is converted to a mixture of [1-(hydroxymethyl)propyl]acetamide (7%) and acetic acid. The product proportions appear to exhibit an equilibrium composition since further heating (14 hours) does not essentially change their distribution. However, when the hydrolysis is carried out in methanol or aqueous ethanol, the hydrolysis is complete within two hours and the acetyl component of the product can be removed by distillation as methyl acetate or ethyl acetate. This procedure not only shortens the hydrolysis time but also avoids salt accumulation in the reaction mixture, converting N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]. Produces dl-2-amino-1-butanol in virtually quantitative yield via methyl)propyl]acetamide and facilitates work-up of the product. Methyl acetate boils at 75°C, so it is easy to distill off. In order to make the process as economical as possible, excessively large amounts of aqueous methanol should be avoided.
If there is an insufficient amount of water ((N-[1-(chloromethyl)propyl]acetimidoyl chloride:
N-[1-(chloromethyl)propyl] when the hydrolysis is carried out using a H ₂ O:MeOH molar ratio of 1:3:3 or less) or especially in the presence of 1,2-dichlorobutane by-product. A small portion (3-15%) of acetimidoyl chloride is hydrolyzed to 2-amino-1-chlorobutane hydrochloride. 2-Amino-1-
The formation of chlorobutane hydrochloride can be completely suppressed by adding water and methanol sequentially and in this order rather than adding them together in one step. N-[1-
(chloromethyl)propyl]acetimidoyl
Addition of water to chloride converts it almost instantaneously to N-[1-(chloromethyl)propyl]acetamide, which is then hydrolyzed via an oxazoline intermediate. Reference Examples 1 to 5, Examples 9 to 20 Three series of reactions (A, B, and C) were carried out using acetonitrile [water concentration (Karl Fischer) = 0.059 to 0.2%] as it was. In each of these series the reaction involves 0.5 moles of butene, chlorine
Performed using 0.5 mol and also acetonitrile:
The _Cl2 molar ratio (equal to the acetonitrile:butene ratio) was varied from 1 to 8. In Series A (1 hour reaction time), the reaction temperature was maintained at 0° C. while simultaneously passing chlorine and butene into the acetonitrile for 1 hour. After removing acetonylyl (40-50℃, 50mm), N-[1-
(chloromethyl)propyl]acetimidoyl
The crude reaction mixture containing chloride and 1,2-dichlorobutane was hydrolyzed by refluxing with aqueous methanol.

[Table] N-[1-(chloromethyl)propyl]acetimidoyl chloride is determined virtually quantitatively.
It is significant to mention that it can be hydrolyzed to [1-(chloromethyl)propyl]acetamide and then to dl-2-amino-1-butanol. Expressing it as dl-2-amino-1-butanol hydrochloride is a very convenient way to express yield. Errors due to volatile components are avoided. dl-1
A small amount of -amino-2-butanol is shown along with dl-2-amino-1-butanol. Even at a low molar ratio of acetonitrile:Cl ₂ of 1, dl-
The yield of 2-amino-1-butanol/HCl is 31%
That's about it. Increasing the acetonitrile:Cl ₂ molar ratio from 1 to 2 improved the yield to 43%, an increase of 12%. Further increasing the acetonitrile: _Cl2 ratio also improves the yield. Each mole increase in acetonitrile up to a total of 5 moles (AN:Cl ₂ ratio 3 to 5) increases the yield of dl-2-amino-1-butanol.HCl by about 6% on average. Note that increasing the amount of acetonitrile (AN:Cl ₂ molar ratio 6 to 8) is significantly less efficient; dl-2-amino-1-butanol/
The average increase in HCl yield is on the order of about 3% per mole of acetonitrile. The approximately 4:1 ratio is a good compromise between yield and a reasonably sized reactor and acetonitrile circulation rate. Both rows B and C contain gaseous reactants.
Passed into acetonitrile for 0.5 hour. The initial reaction temperature was 0°C. This is the highest during the reaction process.
The temperature was allowed to rise to 35°C. Additionally, in Row B, chlorine was passed through the butene acetonitrile solution to maintain a high initial concentration of butene. In train C, both chlorine and butene were passed through the acetonitrile simultaneously to reduce the initial concentration of butene. Simultaneous and sequential addition of butene and chlorine at different acetonitrile/Cl ₂ molar ratios
-[1-(Chloromethyl)propyl]acetimidoyl The results on the yield of chloride are shown in Table 3.

Table: In series B and C, the mass balance shows conversion and recovery data for acetonitrile. In each case the distillate (1,2-dichlorobutane+acetonitrile) was analyzed using gas-liquid chromatography for 1,2-dichlorobutane and acetonitrile. Leaving the N-[1-(chloromethyl)propyl]acetimidoyl, chloride for 40-50 hours before working up yields a less pure product. The data in the table shows that: (1) Crude dl-2-amino-1-butanol.HCl
(or N-1(chloromethyl)propyl]acetimidoyl chloride) mainly depends on the molar ratio of acetonitrile: _Cl2 , and the molar ratio of acetonitrile: _Cl2 :butene to 1:1:
When changing from 1 to 8:1:1, it changes between 31 and 66%. (2) Simultaneous addition of chlorine and butene to acetonitrile is advantageous over the alternative of adding chlorine to a mixture of butene and acetonitrile. The reaction is easier to control as it generates less heat, and dl-2-amino-1
-The yield of butanol/HCl is somewhat better. It is believed that a reaction time of 1 hour generally allows for better control of the exotherm of the reaction. (3) Reaction temperature does not seem to be a controlling factor in determining overall yield. However, N-[1
Taking into account that -(chloromethyl)propyl]acetimidoyl chloride is thermally unstable above 50°C, a reaction temperature between 0 and 25°C is more preferred. This method can be varied depending on batch size. Although the examples are exemplary, for large-scale production it is recommended to operate the process continuously with continuous feeds of butene-1 and chlorine to a stirred continuous reactor. It's probably good. Circulating acetonitrile is continuously distilled and recycled. Such a continuous system allows for higher ratios of acetonitrile to butene-1 and chlorine. On the other hand, for batch processes, it is preferred that the molar ratio of acetonitrile to butene-1 and chlorine is at least 2; molar ratios of 16 or more may require uneconomically large reactors. Even higher ratios are advantageous in continuous methods. Both butene-1 and chlorine are gaseous at room temperature of about 20°C, so low temperatures of about 0°C and below are advantageous, but higher temperatures are preferred if pressurized vessels are available to reduce the need for cooling. Temperature may also be used. The cost of additional refrigeration and pressure vessels will depend on the equipment available. Other modifications within the scope of the invention as defined in the claims will, of course, be apparent to those skilled in the art.

Claims (1)

[Claims] 1. Exists in both liquid and solid phases and is easily hydrolyzed, and in the liquid phase, 3000, 1705, 1430,
The following general formula has infrared absorption peaks at 1370, 1085, 960, 920, 840 and 740 cm ^-1 N-[1-(chloromethyl)propyl]acetimidoyl chloride represented by 2 Reacting at least about 2 moles of acetonitrile with about 1 mole of chlorine and about 1 mole of butene-1 to form N-[1-(chloromethyl)propyl]acetimidoyl chloride and removing excess unreacted acetonitrile. A method for synthesizing N-[chloromethyl)propyl]acetimidoyl chloride, which comprises distilling off under reduced pressure and recycling the separated acetonitrile to a subsequent reaction mixture of acetonitrile, chlorine and butene-1.